1. Field of the Invention
The present invention provides an organic amine salt of monatin and its application as well as a method for resolving the stereoisomers of monatin by forming its salt. More particularly, the present invention relates to a salt form of monatin that is useful as a sweetening agent or as the active ingredient of a sweetener. Within the present invention the salt is formed with an alkylamine, aminoalcohol, amino acid, peptide ester, or the like. The present invention further provides a method for preparing a salt of a particular stereoisomer of monatin with an organic amine by utilizing the difference of crystallinity or solubility of the salt of the stereoisomer of monatin with the organic amine. The use of the salt involves a method for preparing a metal salt of monatin in which the organic amine is replaced by a metal such as sodium, potassium, or the like. The salt includes a single product or a mixture of two or more of the (2S,4S)-isomer, (2S,4R)-isomer, (2R,4R)-isomer and (2R,4S)-isomer of monatin.
2. Discussion of the Background
In recent years, there has been an increased incidence of problems resulting from excessive ingestion of sugar, for example obesity and various types of diseases accompanied thereby. Therefore, development of a low-calorie sweetening agent to serve as a sugar substitute is in high demand. In addition to strength of the sweetness, several additional characteristics and requirements should also be satisfied by the sugar-substitute including: low-calorie, high safety (i.e., little or no side effects), high stability against heat or acid, excellent sweetness quality, and low cost.
Currently, several types of sweetening agents have been used or proposed. For example, aspartame has gained notoriety as a widely used sweetening agent, due to its potent sweetness strength and quality as well as its ease for industrial manufacture on a large scale and its excellent safety. Furthermore, studies on aspartame derivatives have also been extensively conducted. In addition thereto, sweetening materials having various characteristics have been proposed as a sweetening agent and investigations toward the practical use thereof have been conducted. Additional sweetening agents that are currently used include naturally occurring thaumatin, glycyrrhizin, stevioside and the like which are derived from plants and can be collected on a large scale. However, there still exists a strong desire to develop a sweetening material that can be practically employed as a sweetening agent and has a high sweetening strength.
Monatin is a naturally occurring amino acid derivative isolated from root bark of Schlerochiton ilicifolius which is a self-sown plant in the Northwestern Transvaal region of South Africa, and R. Vleggaar et al. (J. Chem. Soc. Perkin Trans., 3095-3098, (1992)), reported its structure as being (2S,4S)-2-amino-4-carboxy-4-hydroxy-5-(3-indolyl)pentanoic acid ((2S,4S)-4-hydroxy-4-(3-indolylmethyl)-glutamic acid). Additionally, according to Vleggar et al. the degree of sweetness of the (2S,4S) isomer referred to as being derived from this natural plant has been reported to be 800 times, or maybe 1400 times of sucrose. There are some methods reported on the synthesis of monatin, but many Although some processes for the synthesis of monatin have been reported, a suitable industrial process has not been reported to date. Examples of synthesis of monatin can be found in South Africa (ZA) Patent Application No. 87/4288, C. W. Holzapfel et al., Synthetic Communications, 24 (22), 3197-3211 (1994), U.S. Pat. No. 5,994,559, and K, Nakamura et al., Organic Letters, 2, 2967-2970 (2000). Therefore, a derivative having a sweetness strength equivalent to or greater than that of monatin, which can be more readily produced than monatin, is desired and would have more feasible practicability as a sweetening agent.
In order to isolate various stereoisomers of monatin to a high purity, a method of crystallization is first conceivable. In this connection, the following methods account for the state of the known art regarding the crystallization of monatin (including the free moatin, salt, and so on).
In R. Vleggaar et al., J. Chem. Soc., Perkin Trans., 3095-3098 (1992), the authors disclose the preparation of the free monantin ((2S,4S) isomer) crystals from a mixture of water, acetic acid and ethanol (1:1:5) and disclose the melting point to be 216-220° C. South Africa Patent Application. No. 87/4288 (P. J. van Wyk et al., ZA 87/4288) disclose the melting point of the free monatin ((2S,4S) isomer) (crystalline solid) to be 247-265° C. (decomposition), though its salts are amorphous solids. Holzapfel et al., Synthetic Communications, 24(22), 3197-3211 (1994), disclose the crystals of a mixture of the synthetic (2S,4S) and (2R,4R) free monatin isomers crystallized twice from a mixture of water and acetic acid (10:1), of which the melting point is 212-214° C.
Accordingly, only the (2S,4S)-isomer and a mixture of the (2S,4S)- and (2R,4R)-isomers of monatin are known as monatin crystals. Moreover, although the existence of the ammonium salt, alkali metal salt and alkaline earth metal is suggested as salts, these salts have never been isolated as crystals and hence never applied to resolution of the optical isomers. In other words, merely a method of utilizing the crystals of free monatin is known as the only method for isolation and purification of crystalline monatin, and the existence of the ammonium salt and a variety of metal salts has merely been suggested as monatin salt. On the other hand, no salt of monatin with an organic amine has been known at all and it is not clear whether such a salt can be prepared or not. Therefore, there is no attempt to make the crystal of the organic amine salt of monatin in order to separate the stereoisomer of monatin or utilize it as a sweetening agent. Accordingly, there now exists a requirement for the development of a method of preparing a salt of monatin with an organic amine and further crystalize the salt, and to develop a method for resolution of the respective stereoisomers of monatin by utilizing the salt or examine the use of monatin as a sweetening agent on a viewpoint of practical use.